Reduced Myofilament Contraction in Human Heart Failure. Insights From Electromechanical Simulations

Abstract

[EN] Intracellular Ca2+ is the main activator of myofilament contraction and the altered Ca2+ handling observed in failing cells has been established as the leading cause of reduced inotropy in heart failure. Electrophysiological studies usually quantify Ca2+ transients to estimate contractile effects. However, heart failure remodeling of myofilaments also occurs, modifying the correlation between Ca2+ and force. The aim of this study was to analyze myofilament tension generated by action potentials in human heart failure. In a ventricular electromechanical model we investigated cellular contraction force associated with intracellular Ca2+ in heart failure by implementing the characteristic electrophysiological, beta-adrenergic, and mechanical changes. Despite the inotropic myofilament remodeling induced by heartfailure, the maximal active tension in failing cells was one third of the force generated in normal cells. With isoproterenol, beta-adrenergic stimulation increased systolic Ca2+, which enhanced myofilament tension by up to 150%, but failing cells also showed a smaller contraction force compared to normal. We observed that contractility was very sensitive to changes in intracellular Ca2+, confirming that increasing Ca2+ peak would improve contraction in heart failure.